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Hereditary developmental orthopaedic diseases pose a serious threat to the quality of life of dogs. The pain as well as the detrimental effect on mobility that can accompany these disorders have a major impact on the dogs as well as their owners. The studies described in this thesis aim to give more insight into the incidence of the most relevant of these diseases, as well as a better understanding of how they develop. This knowledge is crucial in order to devise and maintain effective screening and breeding programs. Between 2002 and 2010 more than 35,000 Dutch purebred dogs were officially screened for hip dysplasia, elbow dysplasia or both. The frequency of hip dysplasia was 15%, and 9% for elbow dysplasia, with substantial differences between breeds. Breeds that were screened most often were the Labrador retriever, Golden Retriever, Bernese Mountain dog and Newfoundland. In these four breeds heritabilities, genetic and residual correlations, and sex predispositions were calculated for these two traits. The breeding progress made using the current selection methods was slight to moderate for hip and elbow dysplasia. Multiple primary diseases are included in the term elbow dysplasia, with fragmented coronoid process being the most frequent form. The phenotypic and genetic correlations between signs of osteoarthritis in certain locations in the elbow joint were calculated and the best radiographic indicator for these traits was determined. Between 1990 and 2007, 3834 Dutch Flat-Coated Retrievers were screened for patellar luxation, 24% of which were affected. A clear sex predisposition was observed with 30% of females affected and only 17% of males. The heritability was 0.17 in this population, indicating that environmental effects have a large impact on the development of this disorder. Breeding progress was initially high, with a reduction of incidence form 28% to 18%, but has stagnated in later years. For both hip dysplasia and patellar luxation, a genome wide association study was performed. For hip dysplasia 48 affected Labrador Retrievers were compared to 30 healthy ones, which resulted in significant association on chromosome 8, and suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Exons in these regions were sequenced and identified several candidate genes which might influence the development of hip dysplasia in this breed. These candidate genes, LAMA2, LRR1 and COL6A3, are involved in differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. For patellar luxation, 45 affected Flat-Coated Retrievers and 40 healthy ones were compared. Significant association was found on chromosome 7, as well as suggestive association on chromosomes 3, 31 and 36. Exons in these regions were sequenced in 15 cases and a pool of controls. More than 7,000 variations were found, 124 of which were genotyped in a cohort of 95 Flat-Coated Retrievers. Nine SNPs, in eight genes, were associated with patellar luxation.

Background: Patellar luxation is an orthopedic disorder in which the patella moves out of its normal location within the femoral trochlea of the knee and it can lead to osteoarthritis, lameness, and pain. In dogs it is a heritable trait, with both environmental and genetic factors contributing to the phenotype. The prevalence of patellar luxation in the Dutch Flat-Coated Retriever population is 24%. In this study, we investigated the molecular genetics of the disorder in this population. Results: Genome-wide association analysis of 15,823 single nucleotide polymorphisms (SNPs) in 45 cases and 40 controls revealed that patellar luxation was significantly associated with a region on chromosome CFA07, and possibly with regions on CFA03, CFA31, and CFA36. The exons of the genes in these regions, 0.5 Mb combined, were analyzed further. These exons from 15 cases and a pooled sample from 15 controls were enriched using custom genomic hybridization arrays and analyzed by massive parallel DNA sequencing. In total 7257 variations were detected. Subsequently, a selection of 144 of these SNPs were genotyped in 95 Flat-Coated Retrievers. Nine SNPs, in eight genes on CFA07 and CFA31, were associated with patellar luxation (P

Canine patellar luxation has been described in various dog breeds, with high prevalence especially in smaller dogs. Most dogs suffer from medial displacement of the patella, although in larger dogs lateral displacement is also seen. A sex predisposition has been described for females. Patellar luxation is considered a polygenic, multifactorial disorder. From 1990 to 2007, in total 3834 Flat-Coated Retrievers were screened; 23.6% of those animals were affected with patellar luxation. Lateral displacement of the patella was most common in this breed (61% of cases), whereas medial (31% of cases) and lateral and medial (8% of cases) were less common. Unilateral involvement (51% of cases) was just as often observed as was bilateral involvement (49% of cases). Females were more often affected with patellar luxation (30% of all tested females) than were males (17% of all tested males). The heritability of patellar luxation was 0.17 ± 0.03 in this population, and breeding with one affected parent increased the prevalence of patellar luxation in offspring by 45% compared to that with two unaffected parents. Since the start of the screening program, there was an initial decrease from 28% to 18% in incidence, but this stagnated thereafter. The annual average estimated breeding values followed the same pattern. With approximately one quarter of the Dutch Flat-Coated Retrievers being affected with patellar luxation, this population shows unusually high prevalence compared with reports in other large-breed dogs. The heritability for patellar luxation in this population was moderate (0.17), indicating that environmental factors play a large role in the manifestation of the disorder. A screening program reduced the prevalence of patellar luxation in this breed, but improvement has recently stagnated. Inclusion of breeding values in the screening program could improve its effectiveness. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics. KEYWORDS: breeding values, genetic trend, heritability, lateral patellar luxation, phenotypic trend, prevalence, sex predisposition